Substituted thiacycloalkeno [3,2-b] pyridines

ABSTRACT

Novel substituted thiacycloalkeno [3,2-b] pyridines are described. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstrictor activity.

This is a division, of application Ser. No. 10,858, filed Feb. 17, 1987now U.S. Pat. No. 4,777,167, which is a continuation-in-part ofapplication Ser. No. 849,647, filed Apr. 9, 1986 now U.S. Pat. No.4,705,785.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain substitutedthiacycloalkeno[3,2-b]pyridines. These compounds are useful as calciumchannel antagonists with cardiovascular, antiasthmatic,antibronchospastic, gastric antisecretory, cytoprotective and plateletaggregation inhibitory activity. In addition, the compounds are usefulin treating hypermotility of the G-I tract and in the treatment ofdiarrhea. This invention also relates to a process for preparing thesecompounds, compositions thereof, methods of use an novel intermediates.

2. Related Disclosure

U.S. Pat. No. 4,285,955 and U.S. Pat. No. 4,483,985 (which is adivisional of the aforementioned patent) disclose acyclic sulfonesubstitution on simple dihydropyridines which possess calcium channelantagonist activity. However, the compounds in question are chemicallydistinct from the compounds of the present invention.

10-Phenyl-2H-thiopyrano[3,2-b]quinolines are disclosed in G. P. A.Pagani, J. Chem. Soc., Perkin Trans. 2,1392-7(1974).

However, these compounds are not calcium channel antagonists.

U.S. Pat. No. 4,532,248 discloses a broad genus of dihydropyridinesincluding cyclic sulfones fused to a dihydropyridine nucleus.Cardiotonic activity is claimed for the entire genus. The compounds ofthe present invention, on the other hand, are potent calcium antagonistswith pharmacologic activity opposite to that claimed in U.S. Pat. No.4,532,248.

SUMMARY OF THE INVENTION

The substituted thiacycloalkeno[3,2-b]pyridines which are the subject ofthis invention have the following general formula: ##STR1## wherein n isan integer from 1 to 12; R₁ is hydrogen, amino, alkyl, haloalkyl or CH₂OR₂ ; R₂ is straight chained or branched alkyl having 1 to 8 carboatoms, cycloalkyl having 3 to 7 carbon atoms, or alkylene-X having atleast 2 carbon atoms, wherein X is alkoxy, hydroxy, halo, p-tosyloxy,mesyloxy, amino, pyridyl or --NR₄ R₅, wherein R₄ and R₅ are the same ordifferent and are selected from hydrogen, alkyl, cycloalkyl, phenyl,benzyl, phenylethyl, or R₄, R₅ and the nitrogen atom to which they areattached form a 5, 6 or 7 membered heterocyclic ring which optionallycontains an oxygen or sulfur atom or an additional nitrogen atom or saidheterocyclic ring may be fused to a benzene ring, as in indoline,isoindoline, tetrahydroquinoline or tetrahydroisoquinoline, and in theinstance wherein said heterocyclic ring is piperazino, said piperazinomay optionally be substituted in the 4-position with the substituent R₆which is selected from alkyl, cycloalkyl, benzyl, phenyl, or phenylsubstituted by alkoxy, halo, alkyl, nitro or trifluoromethyl; R₃ is2-pyridyl, 3-pyridyl, 3-pyridyl substituted at positions 2, 4, 5 or 6with one or more groups selected from halogen, nitro, alkoxy, alkylthio,cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or alkylsulfonyl;2-thienyl, 3-thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzthiadiazolyl orphenyl optionally substituted at positions 2 through 6 with one or moregroups selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy,alkyl-thio, difluoromethoxy, difluoromethylthio, alkylsulfonyl, halo,nitro or trifluoromethyl; or the pharmaceutically acceptable acidaddition salts thereof.

The compounds of this invention are assymetric in the pyridine ring atthe R₃ point of attachment and thus exist as optical antipodes and assuch are part of this invention. The antipodes can be separated bymethods known to those skilled in the art such as, for example,fractional recrystallization of diastereomeric salts of enantiomericallypure acids. Alternatively, the antipodes can be separated bychromatography in a Pirkle column.

Also included in this invention is a process for preparing the compoundsof formula I, said process being disclosed in detail hereinafter.

Also part of the present invention are certain intermediates and theprocess for the preparation thereof.

Preferred compounds of the present invention are:

1. Ethyl2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate.

2. N,N-Dimethylaminoethyl2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate.

3. N-Benzyl-N-methylaminoethyl2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate.

4. Ethyl3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thio-pyrano[3,2-b]pyridine-7-carboxylate.

5. N,N-Dimethylaminoethyl3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano[3,2-b]pyridine-7-carboxylate.

6. N-Benzyl-N-methylaminoethyl3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano[3,2-b]pyridine-7-carboxylate.

7. N-Benzyl-N-methylaminoethyl3,4,5,8-tetrahydro-6-methyl-8-(2,3,4,5,6-pentafluorophenyl)-1,1-dioxo-2H-thiopyrano[3,2-b]pyridine-7-carboxylate.

8. Ethyl9-(2,3,4,5,6-pentafluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

9. N-Benzyl-N-methylaminoethyl2,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1-dioxothiacycloheptano[3,2-b]pyridine-8-carboxylate.

10. N,N-Dimethylaminoethyl2,3,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1-dioxothiacycloheptano[3,2-b]pyridine-8-carboxylate.

11. 2-Methoxyethyl2,3,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1-dioxo-thiacyclohepteno[3,2-b]pyridine-8-carboxylate.

12. N-Benzyl-N-methylaminoethyl9-(2,3,4,5,6-pentafluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

13. Ethyl10-(2,3,4,5,6-pentafluorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate.

14. N-Benzyl-N-methylaminoethyl10-(2,3,4,5,6-pentafluorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate.

15. N-Benzyl-N-methylaminoethyl3,4,5,6,7,10-hexahydro-8-methyl-10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate.

16. N-Benzyl-N-methylaminoethyl 11-(3-nitrophenyl)2,3,4,6,7,8,11-octahydro-9-methyl-1,1-dioxothiacyclononeno[3,2-b]pyridine-10-carboxylate.

17. N-Benzyl-N-methylaminoethyl2,4,5,6,9-hexahydro-6-methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

18. N-Benzyl-N-methylaminoethyl9-(2-chlorophenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

19. N-Benzyl-N-methylaminoethyl9-(2,3-dichlorophenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

20. N-Benzyl-N-methylaminoethyl9-(2-chloro-6-fluorophenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

21. N-Benzyl-N-methylaminoethyl9-(2-cifluoromethoxyphenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

22. N-Benzyl-N-methylaminoethyl2,4,5,6,9-hexahydro-7-methyl-9-(2-trifluoromethylphenyl)-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

23. N-Benzyl-N-methylaminoethyl10-(2-chlorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxocycloocteno[3,2-b]pyridine-9-carboxylate.

24. N-Benzyl-N-methylaminoethyl 10-(b2,3-dichlorophenyl-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

25. N-Benzyl-N-methylaminoethyl10-(2-difluoromethoxyphenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

26. N-Benzyl-N-methylaminoethyl10-(2-chloro-6-fluorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

27. N-Benzyl-N-methylaminoethyl10-(2-chloro-3-trifluoromethylphenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

28. N-Benzyl-N-methylaminoethyl12-(2-chloro-3-trifluoromethylphenyl)-2,3,4,5,6,7,8,11-octahydro-9-methyl-1,1-dioxothiacyclononeno[3,2-b]pyridine-10-carboxylate.

29. N-Methyl-N-phenylaminoethyl10-(2,3,4,5,6-pentafluorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

The compounds of this invention are potent inhibitors of calcium ionuptake into smooth muscle tissue and act to relax or prevent contractionof tissue mediated by calcium mechanisms. The compounds of thisinvention have therapeutic utility in the treatment of cardiovasculardisorders including hypertension, ischemia, angina, arrhythmias,congestive heart failure, peripheral vascular disorders such asintermittant claudication, migraines, myocardial infarction, plateletaggregation and stroke.

In addition, the compounds of the invention possess utility with respectto other disorders such as hypersensitivity, allergy, asthma,dysmenorhea, bronchoconstriction, esophageal spasm, premature labor andurinary tract, gastric hypersecretory and membrane integrity disorders.The compounds, compositions and methods for making the various aspectsof the present invention will become more readily apparent from thefollowing description.

DESCRIPTION AND PREFERRED EMBODIMENTS

Various terms used herein should be understood to signify the following:

Unless specified otherwise, the term "alkyl" refers to a straight,branched or cyclic substituent consisting solely of carbon and hydrogenwith no unsaturation and containing from 1 to 8 carbon atoms. The term"lower alkoxy" refers to a lower alkyl chain as described above havingno more than 4 carbons. The term "halo" means fluoro, chloro, bromo andiodo.

The phrase "pharmaceutically acceptable salts" denotes salts of the freebase which possess the desired pharmacological activity of the free baseand which are neither biologically nor otherwise undesirable. Thesesalts may be derived from inorganic or organic acids. Examples ofinorganic acids are hydrochloric acid, nitric acid, hydrobromic acid,sulfuric acid or phosphoric acid. Examples of organic acids are aceticacid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonicacid, succinic acid, malic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

Pharmaceutical compositions containing a compound of the presentinvention as the active ingredient in intimate admixture with apharmaceutical carrier can be prepared according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., aerosol, intravenous, sublingual, oral or topical.In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like in the case of oral liquid preparations such as, forexample, suspensions, elixirs and solutions; or carriers such asstarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like in the case or oral solidpreparations such as, for example, powders, capsules and tablets.Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe sugar coated or enteric coated by standard techniques. Forparenterals, the carrier will usually comprise sterile water, thoughother ingredients, for example, to aid solubility or for preservativepurposes, may be included. Injectable suspensions may also be prepared,in which case appropriate liquid carriers, suspending agents and thelike may be employed. For aerosol use, suspensions or solutions may beemployed. The pharmaceutical compositions will generally contain perdosage unit, e.g., tablet, capsule, powder, injection, teaspoonful andthe like, from about 0.001 to about 100 mg/kg and preferably from about0.001 to about 20 mg/kg of the active ingredient.

The novel compounds of the present invention may be synthesizedaccording to the following reaction scheme wherein R₁, R₂, R₃, R₄, R₅,are as defined above, MCPBA signifies m-chloroperoxybenzoic acid, and Yis p-methylphenyl or alkyl. ##STR2##

With reference to the above Reaction Scheme, the synthesis of thecompounds of this invention is accomplished as follows:

The 3-keto cyclic sulfones of formula V (in the instance wherein n is1-4) can be prepared in accordance with the procedure disclosed in B.Listert, P. Kuffner, and T. J. Arackel, Chem. Ber. 110, 1069-1085(1977).

However, in the case of 3-oxo-tetrahydrothiophene-1,1-dioxide, that iswherein n is 2, the reference procedure is quite laborious. It has beenfound, in accordance with the present invention, that the compounds offormula V, in which n is 2 or 3, can be obtained in high yield in astraightforward manner from the respective 3-cyclic sulfides of formulaII. Said compound of formula II may be prepared in accordance with theprocedure disclosed in E. A. Fehnel, J. Amer. Chem. Soc. 74, 1569-74(1952).

The 3-keto moiety of compound II is reduced to an alcohol (compound III)preferably with sodium borohydride although a number of other reducingagents such as diborane, lithium aluminum hydride or sodiumcyanoborohydride may be used. Thereafter compound III is oxidized tocompound IV preferably with m-chloroperoxybenzoic acid. Other suitableoxidizing agents are hydrogen peroxide or sodium periodate. Finally, thehydroxy moiety on compound IV is reoxidized to the corresponding ketomoiety in compound V, preferably using Jones reagent (chromic anhydridein dilute sulfuric acid which is added to a solution of the alcohol inacetone). Other suitable oxidizing agents are: potassium dichromatic orCollins reagent (chromic anhydride in pyridine).

The 7, 8 and 9 membered 3-keto cyclic sulfones may be prepared inaccordance with the method described in the Listert et al reference,previously mentioned.

Compounds of the formula I, wherein n is 1-12 (designated compound Ia inthe following Reaction Scheme) may be prepared by stirring equal molaramounts of for example 3-oxotetrahydrothiophene-1,1-dioxide, theappropriately substituted aldehyde of formula VII and the substituted3-aminoester of formula VI in ethanol for two to twenty-four hours atroom temperature (see example 4). The resultant hydroxy intermediate offormula VIII is a novel compound. Said compound VIII is then heated inrefluxing toluene for one to twenty-four hours to effect dehydration,thus producing compound Ia (see example 5).

The 6 to 15 membered cyclic sulfone products of formula I (wherein n is3-12) may be obtained directly by refluxing a stirred ethanolic mixtureof equimolar amounts of the ketosulfone of formula V, the aldehyde offormula VII and the substituted 3-aminoester of formula VI for about 16hours in accordance with the procedure of example 6. The resultantproduct wherein n is 3-12, is designated compound Ib and/or XII. Notethat compound Ib is actually the same as compound Ia, but obtained by adifferent route. Where the novel compound XII is formed, it can beconverted to Ib by heating with ethanolic hydrogen chloride or toluene.

The preparation of compound I wherein R₂ is alkylene-NR₄ R₅ can also beachieved when a compound of the formula V is reacted with an appropriatealdehyde of the formula VII and 2-hydroxyethyl-3-aminocrotonate offormula VIa in order to prepare the intermediate of formula Ic (seeexample VIII). The latter intermediate of formula Ic is then convertedto the sulfonyl ester preferably by refluxing with a compound of theformula IX, wherein Y is p-methylphenyl or alkyl. The sulfonyl ester offormula X is then displaced with an appropriate amine of formula XI inorder to produce a compound of the formula Id (see example 9).

In the following examples, both example 6 and example 10 illustrate thepreparation of compound Ib, by the direct reaction of compound V,compound VII and compound VI, in the instance wherein n is 3-12. VariousReaction Schemes discussed above are disclosed in the followingadditional references:

G. A. Pagani, J. Chem. Soc., Perkin Trans. 2, 1392-7 (1974). K. G.Mason, M. A. Smith, and E. S. Stern, J. Chem. Soc. (C) 2171-76 (1967).

Maruko Seiyaku, Japan No. 58201764 (1984).

The following specific examples are illustrative of the presentinvention and should not be considered as limitative thereof in anymanner.

EXAMPLES Example 1 Tetrahydrothiopyran-3-ol

To a solution of tetrahydrothiopyran-3-one (ref 4) (10.0 g, 0.086 moles)in ethanol was added sodium borohydride (3.25 g, 0.086 moles) over a 5minute period. After stirring for 30 minutes, a 1N. solution ofhydrochloric acid was added until a pH of 5 was reached. The reactionmixture was diluted with water and extracted with dichloromethane (6×50mL). The organic phase was dried over magnesium sulfate, filtered,concentrated in vacuo, and distilled (approx. 100 torr, 158° C.) to give6.8 g product. H' NMR CDCl₃ 3.9 (broad singlet, 1H) 2.2-2.9 (multiplet,5H) 1.4-2.2 (multiplet, 4H).

Example 2 Tetrahydrothiopyran-3-ol-1,1-dioxide

A solution of tetrahydrothiopyran-3-ol (6.8 g, 0.58 moles) andchloroform (250 mL) was cooled to 0° C. and treated withm-chloroperoxybenzoic acid (23.4 g, 0.135 moles) at a rate which did notcause the temperature to rise above 10° C. After addition was complete,the thickened mixture was stirred at 0° C. for 1 hour and then at roomtemperature for 30 minutes. The resulting solid was removed byfiltration and the filtrate evaporated in vacuo. The resulting solid wasdiluted with ethanol and evaporated in vacuo to remove remainingchloroform. The resulting solid was diluted with water (150 mL) andfiltered. The filtrate was evaporated in vacuo and residual water wasremoved by repeated evaporation with toluene. This afforded 7.5 g ofproduct as a colorless oil. H' NMR D₆ -DMSO 4.3 (broad singlet, 1H)3.4-4.0 (multiplet, 1H) 2.7-3.3 (multiplet, 4H) 1.2-2.1 (multiplet, 4H).

Example 3 Tetrahydrothiopyran-3-one-1,1-dioxide

To a solution of tetrahydrothiopyran-3-ol-1,1-dioxide (7.5 g, 0.05moles) and acetone (150 mL) was slowly added enough Jones reagent tomaintain a brown color for at least 10 minutes without need foradditional reagent. The excess reagent was reduced by addition ofisopropanol (5 mL). The mixture was filtered through anhydrous magnesiumsulfate and the chromium salts were washed 3× with acetone. The solventwas removed in vacuo to give a solid which was triturated with ethanol.The resulting crystals were isolated by filtration and rinsed 3× withdiethyl ether. After drying, 5.0 g of product was obtained. H' NMR CDCl₃4.0 (singlet, 2H) 3.3 (triplet, 2H) 2.6 (triplet, 2H) 2.3 (multiplet,2H).

Example 4 Methyl2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxo-thieno[3,2-b]pyridine-6-carboxylate

A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (1.3 g, 0.01 moles),2-nitrobenzaldehyde (1.5 g, 0.01 moles) and methyl 3-aminocrotonate (1.1g, 0.01 moles) in ethanol (20 mL) was stirred overnight. The resultingcrystals were isolated by filtration and washed 2× with ethanol and 2×with diethyl ether. After drying under high vacuum for 24 hours 2.54 gof product was obtained, mp 175°-179° C. (dec).

Example 5 Methyl2,3,4,7,-tetrahydro-5-methyl-7-(2-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate

A mixture of methyl2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate(2.5 g, 0.0065 moles) and toluene (60 mL) was refluxed for 24 hours. Thesolvent was removed in vacuo and the resulting solid was recrystallizedfrom ethanol. The crystals were washed with diethyl ether 2× and driedat 65° C. under high vacuum for 48 hours. This gave 1.78 g product; mp215°-217° C.

Example 6 Methyl3,4,5,8,-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano-[3,2-b]pyridine-7-carboxylate

A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (0.830 g, 0.0056moles), 3-nitrobenzaldehyde (0.846 g, 0.0056 moles) and methyl3-aminocrotonate (0.644 g, 0.0056 moles) in methanol (20 mL) wasrefluxed for 16 hours. After cooling, the resulting solid was isolatedby filtration and washed with diethyl ether. This solid was dried at 40°C. for 4 hours under vacuum to give 0.620 g product; mp 236°-238° C.

Example 7 2-Hydroxyethyl 3-Aminocrotonate

Anhydrous ammonia gas was bubbled through a solution of 2-hydroxyethyl3-oxo-butyrate (25 g, 0.17 moles) (ref 5) and ethanol (250 mL) for 20minutes. This solution was stirred for 16 hours at room temperature. Thesolvent was removed in vacuo and the resulting oil was chromatographedon silica gel (250 g) using ethyl acetate-hexane 60:40 as eluant. Theenriched fractions were combined and the solvent removed in vacuo togive the product; H' NMR CDCl₃ 4.33 (t, 2H) 3.85 (t, 2H) 3.55 (s, 1H)2.85 (broad singlet, 1H) 2.31 (s, 3H).

Example 8 2-Hydroxyethyl3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano[3,2-b]pyridine-7-carboxylate

A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (2.80 g, 0.0189moles), 3-nitrobenzaldehyde (2.85 g, 0.0189 moles),2-hydroxyethyl-3-aminocrotonate (3.28 g, 0.0226 moles), ammonium acetate(0.291 g, 0.0038 moles) and ethanol (35 mL) was refluxed for 16 hours.After cooling to room temperature the resulting solid was isolated byfiltration, washed with ethanol and diethyl ether. The product was driedunder vacuum for 16 hours at room temperature affording the product; mp233°-235° C.

Example 9 N-Benzyl-N-methyl-2-aminoethyl2,3,4,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-5H-thiopyrano[3,2-b]pyridine-7-carboxylateHemioxalate

A mixture of 2-hydroxyethyl3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano[3,2-b]pyridine-7-carboxylate(2.5 g, 0.0061 moles), p-toluenesulfonyl chloride (4.65 g, 0.0244moles), triethylamine (2.46 g, 0.0244 moles) and dichloromethane (25 mL)was refluxed for 4.5 hours. The reaction mixture was cooled and thesolvent removed in vacuo. The resulting oil was chromatographed onsilica gel (170 g) using ethyl acetate-methanol 95:5 as eluant. Theenriched fractions containing the tosylate (H' NMR CDCl₃ 7.3-8.2(multiplet 8H) 6.9 (singlet, 1H) 5.2 (singlet, 1H)) were combined andN-benzyl-N-methylamine (4.69 g, 0.0387 moles) was added to the solution.The solvent was removed in vacuo and the resulting residue was allowedto stand for 72 hours at room temperature. Chromatography of the mixturewas accomplished on silica gel (170 g) using a mixture of ethyl acetateand methanol 97:3 as eluant. The isolated product was dissolved in etherand treated with a saturated solution of oxalic acid in diethyl ether.The resulting solid was collected by filtration, washed with diethylether and dried at 60° C. for 16 hours under vacuum affording theproduct (2.07 g) mp 220°-222° C.

Example 10 Ethyl2,3,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate

A solution of thiacycloheptane-3-one-1,1-dioxide (1.3 g, 0.0080 moles),3-nitrobenzaldehyde (1.2 g, 0.0080 moles), ethyl 3-aminocrotonate (1.04g, 0.0080 moles) and ethanol (20 mL) was refluxed 16 hours. Afterremoval of the solvent in vacuo the residue was chromatographed onsilica gel (170 g) using a mixture of ethyl acetate and hexane (4:1) aseluant. The enriched fractions were combined and the solvent removed invacuo. The solid was triturated with diethyl ether, filtered and driedunder vacuum overnight to give 1.52 g of product; mp 211°-213° C.

Example 11 Ethyl3,4,5,7,10,10a-hexahydro-8-methyl-10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate

A solution of thiacyclooctane-3-one-1,1-dioxide (0.35 g, 0.002 moles),3-nitrobenzaldehyde (0.30 g, 0.002 moles), ethyl 3-aminocrotonate (0.26g, 0.002 moles) and ethanol (30 mL) was refluxed 16 hours. After coolingto room temperature a yellow precipitate formed which was isolated byfiltration, washed with diethyl ether and dried in vacuo to afford theproduct (0.56 g) mp 211°-214° C.

Example 12 Ethyl3,4,5,6,7,10-hexahydro-8-methyl-10-(3-nitrophenyl-1,1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate

A mixture of ethyl3,4,5,7,10,10a-hexahydro-8-methyl-10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate(0.45 g, 0.0011 moles) and toluene (30 mL) was refluxed for 24 hours.The resulting solid was isolated by filtration, washed with diethylether and dried in vacuo to afford the product mp 234°-235° C.

The compounds of the present invention were evaluated for theirbiological properties. The present compounds have shown the ability toinfluence calcium mediated events including inhibition of smooth musclecontraction of trachea and vascular tissues. The model screening regimenused to evaluate these compounds has shown:

(1) Inhibition of nitrendipine binding to calcium channels.

(2) Ability to modulate the activity of tissues which are dependent oncalcium utilization as in trachea and vascular tissue,

(3) Their use as antihypertensive and/or bronchodilating agents inmammals.

Based on the above results, it is believed that these compounds will beuseful in hypertension, myocardial, ischemia, angina, congestive heartfailure, migraine, myocardial infarction, platelet aggregation, stroke,hypersensitivity, allergy, asthma, gastric secretory dysmenorrhea,esophageal spasm, premature labor and urinary tract disorders.

The following Table 1 sets forth inhibition of nitrendipine binding aswell as inhibition of calcium dependent smooth muscle contraction interms of percent inhibition, for a number of representative compounds ofthe present invention.

                                      TABLE I                                     __________________________________________________________________________     ##STR3##                                                                                                                  Inhibition of                                                          Inhibition of                                                                        Ca.sup.2+  dependent                                                   Nitrendipine                                                                         smooth muscle con-                                                     binding                                                                              traction % (μM)               N  R.sub.2             R.sub.3 mp °C.                                                                        IC.sub.50 (μM)                                                                    Inhibition concentration         __________________________________________________________________________    2  CH.sub.3            C.sub.6 F.sub.5                                                                       228-231                                                                              0.15   47         2.0                   2  CH.sub.3            3-NO.sub.2C.sub.6 H.sub.4                                                             198-201                                                                              0.70   76         10.0                  2  CH.sub.3            3-ClC.sub.6 H.sub.4                                                                   196-199                                                                              0.93   --         --                    2  CH.sub.3            3-CHC.sub.6 H.sub.4                                                                   204-205                                                                              2.0    --         --                    2  CH.sub.3            2-NO.sub.2C.sub.6 H.sub.4                                                             215-217                                                                              1.35   63         2.0                   2  CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub. 2 C.sub.6 H.sub.5                                             3-NO.sub.2C.sub.6 H.sub.4                                                             117-123                                                                              1.0    65         5.0                   3  CH.sub.2 CH.sub.3   2-NO.sub.2C.sub.6 H.sub.4                                                             215-217                                                                              1.5    75         10.0                  3  CH.sub.2 CH.sub.3   3-NO.sub.2C.sub.6 H.sub.4                                                             207-209                                                                              0.17   69         10.0                  3  CH.sub.3            3-NO.sub.2C.sub.6 H.sub.4                                                             236-238                                                                              0.16   57         10.0                  3  CH.sub.3            2-NO.sub.2C.sub.6 H.sub.4                                                             291-292                                                                              0.89   84         10.0                  3  CH.sub.2 C.sub.6 H.sub.5                                                                          2-NO.sub.2C.sub.6 H.sub.4                                                             123-126 dec                                                                          3.4    69         10.0                  3  CH.sub.3            C.sub.6 F.sub.5                                                                       242-244                                                                              0.40   46         0.5                   3  CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                              3-NO.sub.2C.sub.6 H.sub.4                                                             220-222                                                                              1.85   46         2.0                   4  CH.sub.3            3-NO.sub.2C.sub.6 H.sub.4                                                             217-219                                                                              0.027, 0.039                                                                         94         2.0                   2  CH.sub.2 CH.sub.3   C.sub.6 F.sub.5                                                                       223-226                                                                              0.56   40         2.0                   4  CH.sub.2 CH.sub.3   C.sub.6 F.sub.5                                                                       202-205                                                                              0.028  95         0.5                   4  CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                              C.sub.6 H.sub.5                                                                       160.165                                                                              0.035  74         0.2                   4  CH.sub.2 CH.sub. 3  3-NO.sub.2C.sub.6 H.sub.4                                                             211-213                                                                              0.044  96         2.0                   4  CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                              3-NO.sub.2C.sub.6 H.sub.4                                                             123-127                                                                              0.13   68         0.2                       ##STR4##                   175-179 dec                                                                          56% @ 8.0                                                                            26         2.0                       ##STR5##                   211-214                                                                              0.27    53%       2.0                   5  CH.sub.2 CH.sub.3   3-NO.sub.2C.sub. 6 H.sub.4                                                            234-235                                                                              0.0055  71%       0.1                   __________________________________________________________________________

    TABLE II      ##STR6##         Inhibition of Trachea Inhibition of Aorta Mass Inhibition of Muscle     Contraction Muscle Contraction     Spectra Nitrendipine binding %     Concentration % Concentration N R X MP MH.sup.+ IC.sup.50 (μM)     Inhibition (μM) Inhibition (μM)       4 3-NO.sub.2 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2 CH.sub.2 NCH.sub.2     CH.sub.2 C.sub.6 H.sub.5 190-194 540 0.29 50 2.0 25 0.1      4 3-NO.sub.2C.sub.6      H.sub.4     ##STR7##      131-134 552 0.860 17 2.0 12 0.1  4 3-NO.sub.2C.sub.6 H.sub.4 CH.sub.2     CH.sub.2 OH 185-187 423 2.40 23 2.0 41 3.0       5     ##STR8##      CH.sub.2 CH.sub.3 180-185 423 0.108 79 0.3 42 0.1  4 3-NO.sub.2C.sub.6     H.sub.4 CH.sub.2 CH.sub.2 NHC.sub.6 H.sub.5 147-150 498 0.016 72 1.0 48     0.1  4 3-NO.sub.2C.sub.6      H.sub.4     ##STR9##      202-204 524 0.100 56 1.0 80 0.1  5 3-NO.sub.2C.sub.6      H.sub.4     ##STR10##      159-165 498 0.065 53 0.1 48 0.1  4 2-CF.sub.3C.sub.6 H.sub.4 CH.sub.2     CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5 135-137 535 0.046 59 0.1 57 0.1 5     2,3-Cl.sub.2C.sub.6 H.sub.3 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2     CH.sub.2 C.sub.6      H.sub.5 162-166 577 0.149 57 1.0 67 0.1 4 2-NO.sub.2C.sub.6 H.sub.4     CH.sub.2 CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5 137-140 512 0.086 57 0.1 43     0.1 5 2-NO.sub.2C.sub.6 H.sub.4 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2     C.sub.6 H.sub.5 144-147 540 0.105 69 0.1 73 0.1  4 3-NO.sub.2C.sub.6     H.sub.4      ##STR11##      141-145 538 0.200 45 0.2 53 0.1  5 3-NO.sub.2C.sub.6      H.sub.4     ##STR12##      184-185 548 0.070 29 0.1 48 0.1  4 2-NO.sub.2C.sub.6 H.sub.4 CH.sub.2     CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5 127-130 540 1.0 41     1.0 7.7 0.1 4 3-NO.sub.2C.sub.6 H.sub.4 CH.sub.2 CH.sub.2 NCH.sub.3     C.sub.6 H.sub.5 186-187 512 0.045 65 1.0 53 0.1 5 C.sub.6 F.sub.5     CH.sub.2 CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5 124-126 571 0.018 47 0.1 63     0.1  4 C.sub.6      F.sub.5     ##STR13##      243-245 524  53 2.0  4 2,3-Cl.sub.2C.sub.6      H.sub.3     ##STR14##      195-197 503  54 2.0      ##STR15##         Inhibition Trachea Inhibition Aorta Mass Inhibition Contraction     Contraction    Spectra Nitrendipine binding % Concentration % Concentrati     on N R MP MH.sup.+ IC.sup.50 (μM) Inhibition (μM) Inhibition     (μM)       4 2-CF.sub.3C.sub.6 H.sub.4 101-104 549 0.16 64 0.1 85 0.1 4 2-Cl,     6-FC.sub.6 H.sub.3 156-162 533 0.029 50 0.1 66 0.1 4 2,5-F.sub.2C.sub.6     H.sub.3 152-160 517 0.12 43 0.1 47 0.1 4 2,3-Cl.sub.2C.sub.6 H.sub.3     150-157 549 0.10 62 0.1 83 0.1 4 3-CF.sub.3C.sub.6 H.sub.4 117-120 549     2.8 37 0.2 44 0.1 4 2-FC.sub.6 H.sub.4 137-140 499 0.44 84 2.0 32 0.1 4     2-NO.sub.2C.sub.6 H.sub.4 144-147 526 0.44 49 0.1 44 0.1 5 C.sub.6     F.sub.5 181-184 585 0.087 50 0.1 70 0.1 4 2-Cl,5-NO.sub.2C.sub.6 H.sub.3     170-173 560 0.26 38 0.1 63 0.1 4 2-ClC.sub.6 H.sub.4 128-134 515 0.22 57     0.1 54 0.1 4 2-Cl,3-CF.sub.3C.sub.6 H.sub.3 168-172 583 0.39 50 0.2 66     0.1 5 2-Cl,3-CF.sub.3C.sub.6 H.sub.3 165-175 597 0.20 57 0.1 78 0.1 5     3-NO.sub.2C.sub.6      H.sub.4 150-154 540 0.045 43 0.1 67 0.1 5 2,3-Cl.sub.2C.sub.6 H.sub.3     155-160 563 0.075 26 0.1 58 0.1 5 2-NO.sub.2C.sub.6 H.sub.4 144-147 540     0.11 48 0.1 73 0.1 6 2-Cl,3-CF.sub.3C.sub.6 H.sub.3 150-155 611 0.47 46     2.0 30 0.1 4 2,6-Cl.sub.2C.sub.6 H.sub.3 160-165 549 0.086 55 0.1 50     0.15 2-OCHF.sub.2C.sub.6 H.sub.4 88-91 561 0.095 76 0.1 80 0.01 4     2-OCHF.sub.2C.sub.6      H.sub.4 130-134 547 0.072 54 0.1

The assay for inhibition of nitrendipine binding follows the followingprocedure:

Female, New Zealand white rabbits (1-2 kg) are sacrificed by cervicaldislocation, and the heart is immediately removed, cleaned, and choppedinto small pieces. The tissue is homogenized in 5×volume of 0.05M Hepesbuffer, pH 7.4. The homogenate is centrifuged at 4000×g for 10 minutes;the supernatant is recentrifuged at 42,000×g for 90 minutes. Theresulting membrane pellet is resuspended (0.7 ml/g weight) in 0.05MHepes, pH 7.4 and stored at -70° C. until used. Each tube of the bindingassay contains ³ H-nitrendipine (0.05-0.50 nM), buffer, membranes (0.10ml), and test compound in a total volume of 1.0 ml. After 90 minutes at4° C., the bound nitrendipine is separated from the unbound byfiltration on Whatman GF/C fibers. After rinsing, the filters are driedand counted in a liquid scintillation counter.

Non-specific binding of ³ H-nitrendipine (that amount bound in thepresence of excess unlabelled nitrendipine) is subtracted from the totalbound to obtain specifically bound radiolabeled nitrendipine. The amountof specifically bound nitrendipine in the presence of a test compound iscompared to that amount bound in the absence of a compound. A percentdisplacement (or inhibition) can then be obtained.

The test for inhibition of calcium dependent smooth muscle contractionis determined according to the following procedure: Trachea from dogssacrificed by excess KCl injection are stored overnight at 4° C. inoxygenated Krebs-Henseleit buffer. Tracheal rings, one cartilage segmentwide (5-10 mm), are cut starting from the bronchial end. After cuttingthe cartilage, the trachealis muscle tissue is suspended in oxygenatedKrebs-Henseleit buffer at 37° C. in a 25 ml tissue bath. After a 60minutes equilibration period, the tissues are challenged with 10 uMcarbachol. After 5 minutes the tissues are rinsed and allowed to rest 50minutes. The tissues are then challenged with 50 mM KCl and, after 30minutes, the contractions are quantitated. The tissues are then rinsedand reequilibrated for 50 minutes. Test compounds are then added for 10minutes, and the tissue is rechallenged with 50 mMKcl. After 30 minutes,the contraction is recorded and used to determine the % inhibition ofcontrol.

The percent inhibition of smooth muscle contraction is calculated fromresponse data before and after drug treatment. ##EQU1## A rating isassigned to the compound depending upon the percent inhibition obtained.

We claim:
 1. A compound of the formula ##STR16## wherein n=1-12; R₁ ishydrogen, amino, alkyl, haloalkyl or CH₂ O--R₂ ; R₂ is straight chainedor branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or alkylene-X having at least 2 carbon atoms, wherein X isalkoxy, hydroxy, halo, p-tosyloxy, mesyloxy, pyridyl, amino or --NR₄ R₅,wherein R₄ and R₅ are the same or different and are selected fromhydrogen, alkyl, cycloalkyl, phenyl, benzyl, phenylethyl, or R₄, R₅ andthe nitrogen atom to which they are attached form a 5, 6 or 7 memberedheterocyclic ring which optionally contains an oxygen or sulfur atom oran additional nitrogen atom, or said heterocyclic ring which optionallycontains an oxygen or sulfur atom or an additional nitrogen atom, orsaid heterocyclic ring may be fused to a benzene ring, and is idoline,isoindoline, tetrahydroquinoline or tetrahydroisoquinoline, and in theinstance wherein said heterocyclic ring is piperazino, said piperazinomay optionally be substituted in the 4-position with the substituent R₆which is selected from alkyl, cycloalkyl, benzyl, phenyl, or phenylsubstituted by alkoxy, halo, alkyl, nitro or trifluoromethyl; R₃ is2-pyridyl, 3-pyridyl, 3-pyridyl substituted at positions 2, 4, 5 or 6with one or more groups selected from halogen, nitro, alkoxy, alkylthio,cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or alkylsulfonyl;2-thienyl, 3-thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzthiadiazolyl orphenyl optionally substituted at positions 2 through 6 with one or moregroups selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy,alkylthio, difluoromethoxy, difluoromethylthio, alkylsulfonyl, halo,nitro or trifluoromethyl; their optical antipodes or pharmaceuticallyacceptable acid and base addition salts thereof.
 2. A compound of claim1 which is methyl2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxo-thieno[3,2-b]pyridine-6-carboxylate.3. A compound of the formula ##STR17## wherein n is an integer from 3 to12, R₁ is hydrogen, amino, alkyl, haloalkyl or CH₂ OR₂ ; R₂ is straightchained or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having3 to 7 carbon atoms, or alkylene-X having at least 2 carbon atoms,wherein X is alkoxy, hydroxy, halo, p-tosyloxy, mesyloxy, amino, pyridylor --NR₄ R₅, wherein R₄ and R₅ are the same or different and areselected from hydrogen, alkyl, cycloalkyl, phenyl, benzyl, phenylethyl,or R₄, R₅ and the nitrogen atom to which they are attached form a 5, 6or 7 membered heterocyclic ring which optionally contains an oxygen orsulfur atom or an additional nitrogen atom, or said heterocyclic ringmay be fused to a benzene ring and is indoline, isoidoline,tetrahydroquinoline or tetrahydroisoquinoline, and in the instancewherein said heterocyclic ring is piperazino, said piperazino mayoptionally be substituted in the 4-position with the substituent R₆which is selected from alkyl, cycloalkyl, benzyl, phenyl, or phenylsubstituted by alkoxy, halo, alkyl, nitro or trifluoromethyl; R₃ is2-pyridyl, 3-pyridyl substituted at positions 2, 4 5 or 6 with one ormore groups selected from halogen, nitro, alkyoxy, alkylthio, cyano,carbalkoxy, difluoromethoxy, difluoromethylthio or alkylsulfonyl;2-thienyl, 3-thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzthiadiazolyl orphenyl optionally substituted at positions 2 through 6 with one or moregroups selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy,alkylthio, difluoromethoxy, difluoromethylthio, alkylsulfonyl, halo,nitro or trifluoromethyl; their optical antipodes or thepharmaceutically acceptable acid and base addition salts thereof.